Our studies of Tregs have revealed that TNF by acting on the TNFR2 receptor, which is highly expressed by Tregs, unexpectedly results in their proliferative expansion and functional activation both in mice and in man. In view of the well known proinflammatory effects of TNF, our data showing that TNF in a more delayed manner can also down-regulate immune responses is rather surprising. One clarification of these contradictory effects of TNF is based on our data showing that TNF by activating Teffector cells also induces them to express TNFR2 and to become more resistant to the suppressive effects of Tregs. Thus, activated T cells at inflammatory sites or in autoimmune status can prevail over the suppressive effects of Tregs. However, as inflammation subsides in healing wounds or in noninflamed tumors Tregs prevail. Most tumor infiltrating T cells (TIL's) actually express TNFR2 and are activated by tumor-derived TNF to be even more immunosuppressive than Tregs in peripheral lymphoid tissues. Suppression of Tregs should enable more effect host anti-tumor responses to become evident. Consequently, our preliminary results show that anti-TNF reduced the growth of mouse Lewis lung and breast (4T1) tumors. Thus, by identifying better means of countering Tregs, we may be able to enhance antitumor responses to tumor vaccines.